Juvenile pemphigus vulgaris: Literature review and a rare case report

Key Clinical Message Pemphigus vulgaris (PV) is a chronic autoimmune blistering disorder characterized by the loss of intraepithelial adhesion affecting the skin and mucous membranes, predominantly affects females in their fifth and sixth decades of life. Due to its rare occurrence in children and adolescents, there is often a delay in diagnosis and treatment in this age group. PV should always be considered in the differential diagnosis of oral ulcerative and vesiculobullous lesions in both children and adolescents.


| INTRODUCTION
Pemphigus refers to a diverse range of chronic blistering conditions that affect both mucous membranes and skin.These disorders are typified by IgG autoantibodies targeting keratinocyte adhesion proteins (desmogleins Dsg1 and Dsg3).The binding of IgG autoantibodies to desmosomal complexes leads to a disruption in intraepidermal adhesion, which causes loss of cell-cell adhesion (acantholysis).This results in the formation of vesicles, blisters, and erosions on the skin and mucous membranes. 1,2Pemphigus vulgaris (PV) is recognized as the most frequently occurring type of pemphigus, accounting for approximately 70% of all cases. 3lthough PV is considered an autoimmune disorder, the specific mechanism of desmosome breakdown after autoantibody binding remains unclear.Multiple theories, such as the steric hindrance theory, desmoglein compensation theory, multiple hits hypothesis, and antibody-induced apoptosis and signaling theory, have been proposed in the literature, but have not yielded conclusive results. 4arious antigenic triggering factors have also been identified that play a role in PV pathogenesis.These include viral infections, genetic factors, thiol group drugs (penicillamine, captopril, and rifampicin), food (such as garlic), vaccines, radiation therapy, pregnancy, micronutrients, and stress. 5,6he worldwide incidence of PV is 0.1-0.5 per 100,000 people per year, however, this varies from 0.17/million/year in France to 6.8/million/year in the United Kingdom.However, the PV incidence in India ranges from 0.09% to 1.8%. 7PV is more common in the Jewish populations, particularly those of Ashkenazi origin, and in the Mediterranean. 5,7,8V exhibits an age and site predilection and typically affects females during their fifth or sixth decade of life. 8pproximately 1.4% to 3.7% of all PV cases are observed in individuals ≤18 years of age.PV in the pediatric group can be categorized as childhood/pediatric PV, affecting those under 12 years of age, and juvenile/adolescent PV, affecting individuals between the ages of 12 and 18 years.The majority of the pediatric pemphigus cases are of the vulgaris type, generally manifesting at approximately 12 years of age. 9ediatric PV cases can pose a diagnostic challenge because of their rarity, and are frequently identified only after a more advanced clinical presentation. 10

| History and clinical examination
History revealed that the patient was apparently well 8 months before when she noticed bullae eruptions in the buccal mucosa that quickly ruptured to form erosive lesions.The erosions were initially painless but became painful over the last 6 months.The medical and family anamnesis was non-contributory, and she denied the intake of any systemic medications.The patient consulted a few private practitioners and was treated conservatively with topical medications.However, the lesions did not respond to conservative therapy.The general physical examination was non-contributory, with no cutaneous, conjunctival, or genital lesions.Intraoral examination revealed diffuse irregular erosive lesions extending bilaterally from the commissure to the retromolar regions on the buccal mucosa along the occlusal line.The erosions were covered with a pseudomembranous slough and surrounded by a mild keratotic zone (Figure 1A,B).Diffuse and ragged erosions were observed bilaterally on the lateral borders of the tongue.(Figure 2A,B).Erosions were also apparent on the ventral aspect of the tongue.(Figure 2C).
A positive Nikolsky sign I (application of mild lateral pressure on the apparently normal mucosa induces the formation of an erosive lesion) was elicited.The lesions were extremely tender and nonindurated on palpation.The patient reported poor oral hygiene and discomfort.Gingival inflammation with bleeding on probing, generalized attrition, and sharp cusps in the posterior mandibular teeth were also observed.

| Differential diagnosis
Pemphigus vulgaris, mucus membrane pemphigoid, bullous lichen planus, herpetic gingivostomatitis, and erythema multiforme were placed in the list of differential diagnoses based on the history of multiple chronic erosions preceded by flaccid bullae formation and a positive Nikolsky sign.

F I G U R E 1 (A) Diffuse, irregular erosions on the right buccal mucosa. (B)
Erosive lesion on the left buccal mucosa along the occlusal plane.

| Investigations
A smear was obtained from the lesion and stained with Hematoxylin and eosin (H & E).It revealed acantholytic cells with peripheral cytoplasmic condensation and large nucleus, while focal areas showed initiation of disruption in cell junctions (Figure 3A).An incisional biopsy including the perilesional tissue from the right buccal mucosa was obtained and submitted for routine histopathological examination and direct immunofluorescence (DIF) testing.Microscopic examination revealed a suprabasilar split in the epithelium, with loss of keratinocyte adhesion (acantholysis).The basilar keratinocytes are intact and form a tombstone pattern.Chronic inflammatory cells (predominantly lymphocytes) were observed in the split and juxta-epithelial regions (Figure 3B).The sections also revealed basilar degeneration in focal areas with an intraepithelial cleft.The upper dermis showed chronic inflammation, along with the focal presence of eosinophils (Figure 3C).The stained section after DIF revealed classic "chicken-wire" or "fish-net" appearance.The white arrow shows intercellular junction staining of the stratified squamous epithelium with IgG (fluorescein isothiocyanate, ×200) (Figure 3D).
5 mL blood sample was collected from the patient and stored at −70°C.The Dsg titers were evaluated using enzyme-linked immunosorbent assay (ELISA) with a kit from Medical and Biological Laboratories Co. Ltd., (Nagoya, Japan) following the manufacturer's instructions.A cut-off value of >20 U/mL was considered as positive.In the present case, Anti-dsg 1 and anti-dsg 3 values were 125.84 U/mL and 193.63 U/mL, thus confirming the diagnosis of Oral PV.A confirmatory PV diagnosis was made based on the characteristic cytological, histopathological, immunofluorescence features, and ELISA titers.

| Treatment
The patient was prescribed a short course of topical steroids in the form of tablet betnesol 1 mg (swish and spit), turbocort oromucosal paste (0.1% w/w), and tablet Celin (vitamin C) three times daily for a week.Depura oral solution (60,000 IU vitamin D3) was also prescribed once a week for 4 weeks.Coronoplasty for sharp tooth cusps was performed and the patient received additional instructions regarding oral hygiene measures.

| Outcome and follow-up
The lesions showed complete resolution after 3 weeks of topical steroid therapy.The steroids were gradually tapered and discontinued (Figure 4A-D).The patient was regularly monitored for 1 year, and no recurrence was reported.

| DISCUSSION
A comprehensive manual and electronic literature search was performed using PubMed and Google Scholar search engines employing following Medical Subject Headings (MeSH) terms, "Pemphigus Vulgaris"[Mesh]) AND ("Child"[Mesh] OR "Adolescent"[Mesh] OR "Pediatrics"[Mesh].The articles published in English language between 2000 to November 2023 were included.Two authors methodologically assessed the titles and abstracts of the retrieved studies/case series/case reports, and any disparity was resolved by a third author.The references of all the included studies were manually checked to include any previously missed studies.A detailed literature research revealed only 53 cases of juvenile PV from 23 articles.The search approach exhibited the following attributes; age, sex, affected site, clinical features, diagnostic aids, treatment protocol, and follow-up (Table 1).
Juvenile/adolescent PV affects individuals between the ages of 12 and 18 years. 9,22,29,33Our findings are in coherence with the published literature.Twenty seven males and 26 females were affected, and the youngest and oldest patients in our review were 12 and 17 years old respectively.
Chronic multiple oral erosions should always raise suspicion for pemphigus, even though erosions may recur in the early stages. 5As the oral mucosa may be the initial site of manifestation, dentists must consider PV in the differential diagnosis and eventually refer to further diagnosis and treatment. 34PV exhibits site predilection that commonly affects the skin and mucous membranes of the oral cavity, genitals, and conjunctiva.Pediatric PV is associated with a higher occurrence of genital and ocular lesions than adult PV. 33 Moreover, the clinical progression of pediatric PV is often more unpredictable than that of adult PV, 2 although it is generally considered to be better than that in adults. 19ur patient presented with exclusive erosive oral lesions at multiple sites.However, genital, ocular, and cutaneous examinations were non-contributory.
The characteristic features of PV include flaccid intraepithelial blisters/bullae that eventually rupture and form painful ulcerations and erosions. 34A detailed history T A B L E 1 Summary of the reported juvenile pemphigus vulgaris cases.
should emphasize the duration of symptoms, number of lesions, and frequency of recurrences. 26About 80-90% of patients develop oral lesions, which are often the first sign in approximately 60% of cases.These lesions often start as a blister/vesicle, and early lesions may appear as a solitary hemorrhagic bulla or shallow, irregular, or ill-defined ulcerations. 5esicles/blisters, which eventually rupture to form erosions, are often observed at sites exposed to mechanical trauma or friction, such as the cheek mucosa, palate, lateral and ventral surfaces of the tongue, floor of the mouth, and lips. 5ntraoral lesions may exhibit a positive Nikolsky's sign due to perivascular edema that disintegrates dermalepidermal junction.However, smaller tense bullous lesions may also exhibit a positive Asboe-Hansen sign/ indirect Nikolsky sign/Nikolsky II. 7Patients with PV patients often complain of profuse salivation and difficulties with chewing and deglutition, as observed in the present case. 35ur patient presented with soreness and burning sensations in the oral cavity.Clinical examination revealed oral erosive lesions at multiple sites, with a positive Nikolsky sign.However, the cutaneous and other mucosal surfaces were not affected.
PV often poses a diagnostic threat if the oral cavity is the only affected site.The rarity of pemphigus lesions in pediatric patients further delays the diagnosis. 19PV should be given a place in the differential diagnosis of chronic erosive lesions of the oral cavity, and the oral physician should be familiar with the characteristic features of PV, thus, differentiating the disease from other erosive oral lesions. 19 comprehensive diagnosis of pemphigus is based on four criteria's-(a) clinical presentation, (b) histopathologic examination of a lesional biopsy, (c) direct immunofluorescence (DIF) examination of a perilesional skin or mucosal biopsy, and (d) Serological detection of autoantibodies against epithelial cell surface by indirect immunofluorescence (IIF) and/or enzymelinked immunosorbent assay (ELISA Dsg1 and Dsg3).36 Serological detection and differentiation of circulating autoantibodies by enzyme-linked immunosorbent assays (ELISA) form the cornerstone of pemphigus diagnostics.37 Diagnostic tests for PV do not differ between adult patients and children, as both have similar clinical, histological, and immunological features.Cytodiagnosis can be a useful, cost-effective, and quick diagnostic aid for ulcerative and vesiculobullous lesions, such as PV and herpes infections.Therefore, it can be used as a routine ancillary diagnostic method.26 In our case, smear revealed acantholysis and acantholytic/Tzanck cells with peripheral cytoplasmic condensation and a large nucleus.
Biopsies from intact vesicles/blisters yield more accurate results, but are infrequently seen as they tend to rupture easily. 26,33Lesional skin samples were used for histopathological examination, and perilesional skin samples were used for direct immunofluorescence to detect tissue-bound autoantibodies. 37cantholysis and blister/vesicle formation within the epithelial layer, just above the basal layer (suprabasilar split), are the characteristic histological features of PV.In some cases, only the basal cells are left projecting into the blister cavity, creating a "row of tombstone" appearance. 1,5,7A relative scarcity of inflammatory cell infiltrates helps to distinguish PV from other bullous diseases, where profuse inflammatory cell infiltration is observed. 5,7 suprabasilar split with acantholytic cells arranged in a tombstone pattern was observed in the present case, with features consistent with PV.
Serological investigations such as indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) have also been conducted to detect autoantibodies against desmoglein glycoproteins. 35The quantitative ELISA titre can also be used to monitor the disease activity and response to treatment, as the antibody titre levels correlate with the disease activity and severity of the disease. 37he DIF findings indicate the presence of IgG antibodies that accumulate in the intercellular spaces, specifically targeting desmoglein proteins, resulting in a distinctive "fish-net" or "chicken-wire" appearance. 5,7If the diagnosis remains unclear, immunoprecipitation and immunoblot analyses may also be performed. 35he primary objective of the therapeutic management of PV is to control the disease, heal mucocutaneous lesions, and minimize the associated functional disability.The therapeutic challenge is to prevent relapses and avoid adverse events associated with prolonged use of steroids and immunosuppressive agents.Thus, close clinical monitoring of the efficacy and safety of treatment is warranted. 38ystemic corticosteroids, either alone or in combination with adjuvant immunosuppressants, have traditionally been employed as treatment strategies for juvenile PV.Nevertheless, administering steroids alone may result in substantial adverse effects such as compromised physical appearance, increased susceptibility to infections, and nutritional deficits. 19ue to the limited number of controlled trials in pediatric PV, there are no approved therapeutic protocols by the Food and Drug Administration, and the existing therapeutic protocols lack substantial evidence.Currently, there are no specific guidelines for therapeutic strategies for this patient population. 19,39ystemic corticosteroids form the cornerstone therapy for PV, while adjuvant therapies such as mycophenolate mofetil, azathioprine, dapsone, cyclophosphamide, and rituximab are used in recalcitrant cases.These current therapies are effective in reducing circulating antibodies and allowing patients to lead their normal lives. 40Prednisolone forms the cornerstone of treatment, and the appropriate dose in the pediatric group should be determined based on factors such as age, weight, severity of the disease, and potential side effects of the medication.The recommended dose of prednisolone is 0.5-1 mg/kg, which is gradually tapered to the lowest effective dose to minimize any associated adverse effects. 9,19,26,34The steroid dosage may be modified based on the patient's clinical outcome, with gradual tapering in patients showing substantial resolution. 19,33Oral PV cases may be successfully treated with a short course of low-dose corticosteroids without the need for additional therapy, as was the case with our patient. 26owever, long-term steroid therapy is associated with adverse effects, such as obesity, growth retardation, osteoporosis, hormonal irregularities, and altered menstrual cycles.Therefore, alternative steroid-sparing treatments and innovative therapeutic strategies to eradicate blisters at the molecular level are being actively sought. 40he prognosis of pediatric PV is generally better than that of adults; however, it may still be guarded owing to the potential adverse effects of corticosteroids and adjunctive immunosuppressants.Pediatric PV patients with extensive skin involvement (>70%), pneumonia, sepsis, and electrolyte imbalances are associated with mortality. 9,26

| CONCLUSIONS
The rare occurrence of PV in the present case emphasizes the importance of considering PV as a possible differential diagnosis for vesiculobullous lesions in children and adolescents.PV may manifest with exclusive oral manifestations, and oral physicians should be familiar with the characteristic oral manifestations.A detailed history and clinical examination, coupled with histopathology and immunofluorescence, form the cornerstone of an early diagnosis and management.

F
I G U R E 2 (A-C) Ragged erosions covered by fibrin slough on the tongue.F I G U R E 3 (A) Tzanck smearreveals acantholytic cell.(B) Revealed a suprabasilar split and a tombstone pattern.(C) Showing the disrupted cellular junction projections towards the split.(D) Revealing the characteristic "chicken-wire" or "fish-net" appearance.